We evaluated three treatment modalities for Gram-negative septic shock in a canine model; reconstituted human high-density lipoprotein, monoclonal antibodies specific for the O-polysaccharide and core regions of the bacteria used for challenge and N-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis. When human high-density lipoprotein was administered during Gram-negative sepsis, there was improvement in leukopenia and a decreased endotoxemia and circulating levels of tumor necrosis factor. However, this preparation produced hepatic and neurologic toxicity. In the second study, monoclonal antibodies specific for the O- polysaccharide of the challenge bacteria significantly reduced bacteremia and endotoxemia but not serum tumor necrosis factor. Monoclonal antibodies specific for the core of the endotoxin molecule significantly increased mean arterial pressure but did not significantly affect other parameters. Lastly, administration of L-NMMA effecting non-selective inhibition of nitric oxide production, was not beneficial in endotoxemic dogs.